Cells exposed to elevated temperatures or certain chemical agents respond to such stress by inducing the synthesis of a small set of proteins. This cellular response is termed a "heat shock response." The proteins synthesized in response to stress are termed "heat shock proteins" or "HSP." The heat shock response is believed to be ubiquitous, and has been observed in prokaryotic as well as eukaryotic cells and organisms (including man). The synthesis of the heat shock proteins is highly significant since failure to produce these proteins in response to stress is associated with cell death and with tissue and organ injury. The heat shock proteins are believed to play a role in attenuating the severity of the stress, and, in thereby returning the affected cell to a quiescent state. Excellent reviews of the heat shock phenomenon are provided by Lanks, K. W. (Exper. Cell Res. 165:1-10 (1986)) and Lindquist, S. (Ann. Rev. Biochem. 55:1151-1191 (1986)), which references are hereby incorporated by reference.
The heat shock proteins have been found to possess functions which are unrelated to, and independent of, their role in the heat shock phenomenon. The genes which encode the heat shock proteins (i.e. hsp genes) have been found to be differentially expressed during embryonic development (Bensaude, O. et al., Nature 305:331 (1983)), during differentiation of specific cell types such as myoblasts, embryonal carcinoma, and erythroid cells (Atkinson, B. G., J. Cell. Biol. 89:666 (1986); Atkinson, B. G. et al., Can. J. Biochem. Cell. Biol. 61:404 (1983); Morange, M. et al., Molec. Cell. Biol. 4:730 (1984); Singh, M. K. et al., Nature 309:631 (1984)). Neoplastic transformation is also associated with a change in the level of the heat shock proteins (Lanks, K. W., Exper. Cell Res. 165:1-10 (1986)).
The genes for the heat shock proteins have been found to possess highly conserved 5' sequences which contain a rotationally symmetric consensus sequence known as the "Heat Shock Element" or "HSE". A heat shock transcriptional factor ("HSTF" or "HSF") has been identified which is believed to bind to the HSE sequences, and to play a role in the transcription of the genes which encode the heat shock proteins (Lindquist, S. (Ann. Rev. Biochem. 55:1151-1191 (1986); Parker, C. S. et al., Cell 36:357 -369 (1984); Parker, C. S. et al., Cell 37:253-262 (1984); Wu, C., Nature 286:854-860 (1980); Wu, C., Nature 309:229-241 (1984); Wu, C., Nature 317:84-87 (1985)). As such, this factor is capable of regulating and augmenting the heat shock response of an individual.
Thus, this factor, and agents which promote the activity of this factor, provide a therapy for diseases which are associated with the heat shock response. Because this factor has not been sufficiently characterized to permit its use in the therapy for such diseases, or the permit the identification of agents which promote its activity, it has not previously been possible to employ HSF (or such agents) as the basis for a treatment of such diseases. Thus, a need exists for a means for purifying and producing HSF and its derivatives, antagonists, and agonists.